In Vivo Effects of a GHR Synthesis Inhibitor During Prolonged Treatment in Dogs

Area of Science:

• Pharmacology
• Endocrinology
• Oncology

Background:

• Growth hormone receptor (GHR) activation is crucial for body growth.
• Defective GHR signaling is linked to Laron dwarfism, low IGF-1, and reduced cancer/diabetes risk.
• A small molecule (C#1) was identified to inhibit GHR mRNA translation in vitro.

Purpose of the Study:

• To evaluate the in vivo efficacy and toxicity of C#1 in Beagle dogs.
• To determine if C#1 can achieve plasma concentrations inhibiting cell proliferation without toxicity.
• To assess C#1's potential as an anticancer drug.

Main Methods:

• Beagle dogs were treated daily with 0.1 mg/kg of C#1 for 90 days.
• Clinical monitoring, blood sampling (plasma C#1, CBC, clinical chemistry, endocrinology) were performed.
• Gross and histopathological analyses were conducted post-euthanasia.

Main Results:

• Daily C#1 administration maintained plasma concentrations around 50 nmol/L.
• Two out of six dogs showed decreased appetite, food refusal, and occasional diarrhea.
• Plasma IGF-1 decreased by 31% and GH by 51%; GHR inhibition in vivo was not confirmed.
• No significant effects on glucose, lipid, or folate/homocysteine metabolism were observed.

Conclusions:

• The dose of 0.1 mg C#1/kg/day induced toxic effects, preventing dosage escalation.
• Concomitant decreases in IGF-1 and GH precluded confirmation of in vivo GHR inhibition.
• Developing safer GHR synthesis inhibitors similar to C#1 is a promising strategy for cancer therapy.